Angiogenesis is an integral component of tissue remodeling during a variety of normal and pathological events, such as the female reproductive cycle, fetal development, wound healing, inflammation and tumor progression (Han, Z. C., and Y. Liu, Int. J. Hematol, 70(2):68 (1999); Folkman, J., Nat. Med., 1(1):27 (1995)). The growth of microvessels involves the coordinated migration, proliferation, differentiation and morphogenetic organization of endothelial cells (“EC”) into new capillary structures. Further stabilization and maturation of neovessels occurs through the recruitment of adjacent mesenchymal cells to the vessel walls (Bussolino, F. A., Trands Biochem Sci., 22(7):251 (1997)). The maintenance of developing and quiescent vessels critically depends on the availability of appropriate survival signals. These angiogenic events are orchestrated by a network of extracellular factors, including several classes of cytokines, extracellular matrix and integrins, and by their cognate receptors.
A number of known angiogenic regulators belong to the Tumor Necrosis Factor (TNF) family. Ligands of this family are expressed as type II membrane proteins which may be proteolytically cleaved to produce soluble cytokines (Smith, C. A. et al., Cell, 76:959 (1994)). These ligands trigger biological activities by binding and signalling through their corresponding receptors in the TNF receptor family. The majority of the TNF family members mediate host defense, inflammation and immunological regulation (Vassalli, P., Annu Rev Immunol, 10:411 (1992); De Togni, P. J. et al., Science, 264(5159):703 (1994); Nagata, S., and Goldstein, P., Science, 267:1449 (1995); Foy, T. M. et al., Annu Rev Immunol, 14:591 (1996); Mackay, F. et al., J Exp Med, 190(11)1697 (1999)). In addition, some of these ligands, including TNF-α, Fas ligand (FasL), Vascular Endothelian Growth Inhibitor (VEGI) or TL1, and TWEAK have been shown to regulate EC functions (Frater-Schroder, M. W. et al., Proc. Natl. Acad. Sci. USA, 84:5277 (1987); Yoshida, S. et al., Mol Cell Biol, 17(7):4015 (1997); Ruegg, C. et al., Nat Med, 4(4):408 (1998); Fajardo, L. F. et al., Am J Pathol, 140(3):539 (1992); Leibovich, S. J., Nature, 329(6140):630 (1987); Biancone, L., J Exp Med, 186(1):147 (1997); Yue, T. et al., J. Biol. Chem., 274:1479 (1999); Zhai, Y., et al., Faseb J, 13(1):181 (1999)). The effects of TNF-α on EC behavior are complex. TNF-α inhibits EC growth yet induces capillary tube formation in vitro (Frater-Schroder, M. et al., Proc. Natl. Acad. Sci. USA, 84:5277 (1987); Yoshida, S. et al., Mol Cell Biol, 17(7):4015 (1997)). It also can be antiangiogenic in the context of solid tumors (Ruegg, C. A., Nat Med, 4(4):408 (1998)) or angiogenic in corneal settings in vivo (Frater-Schroder, M. et al., Proc. Natl. Acad. Sci. USA, 84:5277 (1987); Yoshida, S. et al., Mol Cell Biol, 17(7):4015(1997); Fajardo, L. F. et al., Am J Pathol, 140(3):539 (1992); Leibovich, S. J. et al., Nature, 329(6140):630 (1987)). Fas/FasL interaction can induce endothelial capillary tube formation in vivo, probably by triggering the production of heparin-binding growth factors (Biancone, L. et al., J Exp Med, 186(1):147 (1997)), while VEGI inhibits EC survival and proliferation (Zhai, Y. et al., Faseb J, 13(1):181 (1999); Yue, T. et al., J. Biol. Chem., 274:1479 (1999)). TWEAK, a novel member of the TNF ligand family (Chicheportiche, Y. et al., J Biol Chem, 272(51):32401 (1997)), induces the expression of the angiogenic chemokine Interleukin-8 (IL-8) in some epithelial tumor cell lines. Recently, TWEAK was reported to induce both proliferation of cultured human ECs under reduced growth factor conditions and corneal neovascularization (Lynch, C. N. et al., J. Biol. Chem., 271(13):8455 (1999)).
Through the use of expression cloning, a receptor protein for TWEAK has recently been identified as “Fn14.” This protein was originally characterized as an FGF-1 induced immediate early response gene (J. Biol. Chem. 274:33166-33176 (1999) and WO 98/55508). Fn14 has a more restricted expression pattern in adult tissues (as compared to TWEAK) and is the smallest TNF receptor described to date, with only one cysteine-rich repeat.